Approach to Patients with Neurometabolic Diseases Who Show Characteristic Signs and Symptoms

Neurometabolic disorders are hereditary conditions mainly affect the function of the brain and the nervous system. The prevalence of these disorders is 1 in 1,000 live births. Such disorders, at different ages, could manifest as sepsis, hypoglycemia, and other neurologic disorders. Having similar manifestations leads to delayed diagnosis of neurometabolic disorders. A number of neurometabolic disorders have known treatments; however, to prevent long-term complications the key factors are early diagnosis and treatment. Although a large number of neurometabolic diseases have no treatment or cure, the correct and on-time diagnosis before death is important for parents to have plans for prenatal diagnosis. Different diagnostic procedures could be offered to parents, enzymatic procedures, and determining metabolites in plasma, urine, and CSF, and molecular genetic diagnosis. Molecular genetic diagnostic procedures are expensive and could not be offered to all parents. Therefore, we aimed to design algorithms to diagnose neurometabolic disorders according to some frequent and characteristic signs and symptoms. By designing these algorithms and using them properly, we could offer diagnostic enzymatic panels. These enzymatic panels are inexpensive; thereby reducing the financial burden on the parents. Also, having an early diagnosis according to these panels could lead to offering more accurate and less expensive molecular genetic tests.


Introduction
Neurometabolic diseases are a group of disorders mainly affect the brain and the nervous system. 2. Neurometabolic diseases mainly cause defective energy production. 3. Neurometabolic diseases mainly cause defective metabolism of complex molecules.
A number of neurometabolic diseases have definite treatment; however, to prevent devastating and longterm complications, the key prognostic factors are early diagnosis and treatment. To diagnose these disorders, in addition to a high index of clinical suspicion, the clinicians who deal with these disorders need to confirm the diagnosis using sophisticated genetic tests. However, genetic tests usually are delayed and expensive; therefore, many of these genetic tests could not be offered to parents.
According to a number of signs and symptoms, clinicians could request a number of enzymatic tests from plasma, urine, and cerebrospinal fluid (CSF) that always are confirmatory. These enzymatic tests are also inexpensive compared to genetic tests. In this review, we aimed to design simple algorithms using several characteristic signs and symptoms.
According to these algorithms, we could propose diagnostic enzymatic panels for early diagnosis in different groups of neurometabolic disorders. In every section, we begin with a characteristic sign or symptom.    To offer the appropriate enzymatic panel , table 1 must be reviewed precisely.

Chronic subdural effusion and hematomas
Chronic subdural effusion and hematomas could be found in a number of neurometabolic disorders. The list of these neurometabolic disorders is not long and this finding could be approached effectively to differentiate these kinds of neurometabolic disorders ( Figure 2). Table 2 shows these neurometabolic disorders and the main diagnostic procedures. (11,(24)(25)(26)(27)(28)(29)(30)(31) Iran J Child Neurol. Summer 2020 Vol. 14 No. 3

Approach to Patients with Neurometabolic Diseases Who Show Characteristic Signs and Symptoms
Iran J Child Neurol. Summer 2020 Vol. 14 No. 3

Alopecia and global developmental delay
A number of neurometabolic disorders could manifest with alopecia as a definitive sign in addition to global developmental delay. (30) Many of these have curative treatment; therefore, early diagnosis is mandatory to prevent longterm complications. Table 3 shows these neurometabolic disorders and their diagnostic approach. (5,11,15,30,32) Algorithm 3 shows the diagnostic approach to neurometabolic disorders with alopecia and global developmental delay.

Approach to Patients with Neurometabolic Diseases Who Show Characteristic Signs and Symptoms
Iran J Child Neurol. Summer 2020 Vol. 14 No. 3 As shown in algorithm 3, in every patient with alopecia and global delay, we need to rule out hypothyroidism and Vit D-dependent rickets, then all we need are urine organic acid analysis using GC/MS and biotinidase activity. (29,30)

Extensive and long-lasting Mongolian spots (diffuse melanocytosis)
Mongolian spots are congenital dermal melanocytoses that could normally be found on the back and the buttock regions in neonates. They disappear shortly after birth; however, when they are diffuse and extensively involve the skin, clinicians must consider a number of neurometabolic diseases (Figure 2). (17,33) Table 4 shows the neurometabolic diseases with extensive Mongolian spots and the involved enzymes.

Approach to Patients with Neurometabolic Diseases Who Show Characteristic Signs and Symptoms
Iran J Child Neurol. Summer 2020 Vol. 14 No. 3 As has been shown in algorithm 4, to approach extensive Mongolian spots, clinicians should seek other findings such as dysmorphism and corneal opacity. The brain MRI could also help to differentiate neurometabolic diseases with extensive Mongolian spots.
In the rest of this paper, we review the diagnostic approach to a number of laboratory and imaging findings that are characteristic of neurometabolic disorders.

Hyperammonemia
Ammonia is the endproduct of amino acids' catabolism, and its abnormal high levels are toxic to the brain and the nervous system. To excrete ammonia, mammals use the urea cycle. The urea cycle is a complex cycle that needs more than five key enzymes to work efficiently and to transform produced ammonia to less toxic metabolites in the body. Measurement of ammonia level is mandatory in every patient with encephalopathy who might suffer from neurometabolic disorders.
Neonates with hyperammonemia could present with progressive lethargy, vomiting, hypotonia, and seizures mainly after feeding. In older infants and children, hyperammonemia could present with ataxia, decreased consciousness, agitation, and irritability finally, might lead to coma. In all patients with unexplained encephalopathy, serum ammonia should be measured as soon as possible. Table 5 shows the main causes of hyperammonemia and the involved enzymes. (1,11,27,34)

In conclusion
In this short review, we showed that many neurometabolic disorders could be simply diagnosed by having a diagnostic plan after finding cherry-red spot, alopecia and global delay, and extensive Mongolian spot in the neurologic examination of the patient. We also

Hypertyrosinemia
Tyrosine is the precursor for a bunch of neurotransmitters such as dopamine, norepinephrine, and epinephrine. It is also found in the structure of thyroxin and melanin.